目的 研究毒性剂量暴露下聚乙二醇化重组人胰岛素注射液（PEG-Det）的毒动学（TK），以评价系统暴露与剂量、时间及毒性结果之间的关系，通过重复给药分析药物在体内是否存在蓄积及代谢方式是否改变等特性。方法 32只健康Beagle犬随机分为4组，每组8只，雌雄各半，分别sc低、中、高剂量（37.5、75.0、150.0 μg/kg）PEG-Det及溶媒，每周给药2次，重复给药9个月。分别于首次（d1）、中期（d89）和末期（d260）给药后采用放射免疫分析（RIA）法检测不同时间血药浓度，采用罗氏血糖仪同步测定动物血糖水平。试验数据采用DAS 3.0药动程序拟合分析并计算TK参数。结果 各剂量组动物sc给药后，随血药浓度升高伴随血糖降低，且与给药剂量呈正相关；随给药频率增加，血糖降低幅度减小；单次和多次给药后，PEG-Det的C_max和AUC与剂量均呈正相关；随给药频率增加，各剂量组的C_max和AUC_ss降低，且给药末期（9个月）的蓄积指数（R_Cmax和R_AUC）均小于1；各剂量组在给药不同阶段的消除半衰期t_1/2z为20~30 h；达峰时间T_max和清除率CL_z/F均在一定范围内波动，不与剂量相关。结论 Beagle犬重复sc给予PEG-Det 37.5、75.0、150.0 μg/kg，随给药剂量增加，药物暴露量增大；经多次给药后，血浆中胰岛素浓度趋于平稳，体内无药物蓄积；且血糖降低幅度减少，在维持有效浓度和药效的基础上，降低了由低血糖带来的安全性风险。

Objective To study toxicokinetics of pegylated recombinant human insulin injection (PEG-Det) at the toxic dose, and to evaluate the relationship between systemic exposure and dose, time or toxicity outcomes. The existence of drug accumulation and the change of drug metabolism characteristics in vivo are explored by multiple administration of the drug. Methods Tatolly 32 healthy Beagle's dogs were randomly divided into four groups, including low, medium and high dose (37.5, 75.0 and 150 μg/kg) groups of PEG-Det, and vehicle control group. Each group included 8 Beagle's dogs, with male and female animals each half. All animals were sc administered twice a week with continuous dosing for 9 months. The plasma concentration of PEG-Det in period of first day (d1), mid-term (d89) and late-term (d260) dosing was determined using a radioimmunoassay (RIA) method. Meanwhile, the blood glucose level was monitored using a Roche blood glucose meter. The toxicokinetic parameters were calculated by DAS 3.0 software. Results After drug administration, the blood glucose which was positively correlated with the dose decreased along with elevated plasma concentration of PEG-Det. But with increasing of dosing times, the reduction amplitude of blood glucose diminished. The C_max and AUC of PEG-Det were both positively correlated with the dose after single or multiple drug administration. And the C_max and AUC_ss of different dose groups reduced with increasing of dosing times. The accumulation indexes (R_Cmax and R_AUC) were both less than one after nine months dosing, indicating that there was no drug accumulation in vivo of Beagle's dog. The mean elimination half-life t_1/2z ranged from 20 to 30 h, which displayed its characteristics of long-lasting effect. The peak concentration arrival time T_max and clearance CL_z/F fluctuated within a certain range, and were independent of dose. Conclusion Beagle's dogs are sc treated with PEG-Det at different doses of 37.5, 75.0, and 150.0 μg/kg for 9 months. With the increase of dose, drug exposure could increase. After multiple dosing, the plasma concentration of insulin trends to be stable. There is no drug accumulation in vivo. The reduction amplitude of blood glucose reduces, which lowers the safety risks of hypoglycemia on the basis of maintaining the effective concentration and efficacy.

天津创新药物安全评价技术平台（2013ZX09302301）